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Anaphylactoid Purpura, Polyarteritis Nodosa and Purpura Fulminans
ANAPHYLA£TOm PURPURA, POLYARTERITIS NODOSA AND PURPURA FULMINANS WARREN F. DODGE, M.D. LUTHER B. TRAVIS, M.D. C. W. DAESCHNER, M.D.
As experience with the collagen diseases increases, one is frequently impressed by the lack of consistent definitions between them and the consequent difficulty in assigning a specific diagnosis to the patient's problem. Although anaphylactoid purpura, purpura fulminans and polyarteritis nodosa are usually considered to be separate entities, they may have several clinical manifestations in common. For example, anaphylactoid purpura and purpura fulminans characteristically present with an erythematous and sometimes purpuric skin rash involving principally the legs; all three syndromes are likely to be found in the wake of acute infectious processes; and each may demonstrate articular, visceral and renal involvement. The histologic changes in all are characterized by a perivasculitis varying from an infiltrative process with local hemorrhage in anaphylactoid purpura to a gangrenous process in some patients with purpura fulminans and polyarteritis nodosa. These and other considerations to be mentioned later seem to justify including the three syndromes in the same discussion. ANAPHYLACTOID PURPURA
This disease has been known by an unusually wide variety of synonyms: purpura rheumatica, Schoenlein's purpura, Henoch's purpura, From the Division of Renology and Metabolism, the Department of Pediatrics, University of Texas Medical Center, Galveston.
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nonthrombopenic purpura, Osler's syndrome, primary purpura, allergic purpura, vascular anaphylactoid purpura, acute vascular purpura, Schoenlein-Henoch syndrome and anaphylactoid purpura. Today, Henoch-Schoenlein syndrome and anaphylactoid purpura are the terms most commonly used. The clinical picture is characterized by nonthrombopenic purpura, most prominent over the lower part of the trunk, hips and legs, by crises of abdominal pain often associated with melena, by arthralgia, and by urinary findings resembling those of acute nephritis. Low-grade fever is common before the onset, but does not seem to be part of the clinical syndrome. These signs and symptoms may present in any order, and the severity of individual components may vary from absent to being the dominant feature of the patient's illness. Etiologic Factors
Although the etiology of anaphylactoid purpura, like that of other collagen diseases, is unknown, there are certain circumstantial factors which strongly suggest a hypersensitivity state. 6 , 9, 12, 17 In three large surveys of anaphylactoid purpura in childhood2, 12, 18 the age at onset was found to vary from six months to 16 years, with the peak risk between four and five years of age. There is a moderate preponderance of male patients in most reports. The syndrome is rare in the Negro, but this may represent diagnostic failure because of skin color or sampling error in hospitals serving predominantly white patients.2, 18 There seems to be a definite seasonal incidence, fall and spring periods showing the peak number of admissions. 2, 13 Many substances and conditions have been suspected as etiologic factors. These children tend to have a history of major allergic conditions approximately twice that of the general population (14 versus 7 per cent).2 Studies of the family allergic history have been disappointing. Alexander and Eyermann1 were the first to establish food allergies and included milk, egg, chocolate and beans as possibly significant. Various medications, particularly aspirin and the antimicrobials, have been reported as causative agents. In one of our own patients the onset of symptoms followed an injection of penicillin G, and in this subject a significant titer of penicillin antibodies was demonstrated (agar gel diffusion technique). Studies of the patient's family history are usually unrewarding,2 though isolated reports of rheumatic fever, rheumatoid arthritis and anaphylactoid purpura in other members have been noted. In this respect the presence of the nephrotic syndrome, documented milk allergy, and severe asthma, respectively, in the three siblings of one of our patients seems more than coincidental.
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History of a recent acute infectious process can be found in approximately two thirds of patients with anaphylactoid purpura. Although beta hemolytic streptococcal infections have been suspected on the basis of circumstantial evidence, studies of patients have failed to show serologic evidence of significant degree. For example, Komrower7 in England found an increased incidence of rheumatic fever, acute glomerular nephritis and anaphylactoid purpura during an epidemic of beta streptococcal infections during 1953-54. Rubin15 reports that 70 per cent of his patients had beta streptococci in throat culture at the time of admission, while Starky16 found only 34 per cent and states that only 3 per cent of his 103 patients had significant increase in antistreptolysin 0 titer. Vernier17 and associates studied this problem and concluded that the incidence of increased (33 per cent) antistreptolysin 0 titer in their 39 patients was not higher than that which would be found in patients with nonstreptococcal illness. Although it seems unlikely that the streptococcus is the principal etiologic factor, its role is yet to be clearly defined. The 90 per cent incidence of some acute infectious process preceding the onset of anaphylactoid purpura in children strongly suggests that they play an inciting, if not etiologic, role. Clinical Manifestations
SKIN AND SUBCUTANEOUS TISSUES. The characteristic skin involvement is at present essential to the diagnosis (see Fig. 3). The skin lesions are most often urticarial at onset, then fade into erythematous macules or papules, often developing a pinhead-sized hemorrhagic center or progressing to "bruiselike" ecchymoses 1 to 4 cm. in diameter. The sites of predilection are the feet, ankles, legs, buttocks and lower part of the trunk, while lesions above the waist and on the arms are uncommon. This distribution suggests reduced vascular integrity and also helps to distinguish anaphylactoid purpura from the thrombopenic purpuras. Rare examples are described in which the purpuric skin lesion progresses to cutaneous necrosis or even a gangrenous extremity,32 but in the present author's opinion these cases are more properly classified as purpura fulminans. The purpuric and other cutaneous manifestations may precede or follow the other clinical findings and are occasionally so mild that they are not recognized. Several authors suggest that skin lesions may indeed be entirely absent, thus making accurate diagnosis difficult and hazardous. In typical patients the urticarial phase is transient, and purpura continues for only a few weeks, but in some patients the purpura may be recurrent or persistent over a period of years. Coincident in time, but separate in location, are the areas of painful,
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brawny, local edema which occur in over half of patients· with anaphylactoid purpura,2 principally in subjects under three years of age. This manifestation shows a predilection for the dorsum of the hands, feet and scalp and is sometimes quite painful. It may be perplexing unless recognized as part of the anaphylactoid purpura syndrome. Recurrence of the rash is not uncommon, whereas recurrence of the painful local areas of edema is rare. Histologically, Vernier and others17 have shown that the hemorrhagic skin lesion is characterized by perivascular infiltrations about the small blood vessels of the dermis with plugging of some vessels by leukocyte-platelet thrombi. JOINTS. Periarticular pain, tenderness or swelling is the second most common finding, being present in approximately two thirds of the patients.2 The joints most often involved are the ankle and knee, less frequently the wrist and fingers. There seems to be a tendency for more prominent skin lesions in the involved articular areas. The joint symptoms may resemble those of acute articular involvement in lupus erythematosus, rheumatic fever or rheumatoid arthritis. They vary in severity from periarticular pain without objective findings to acute local swelling, tenderness and reduction of joint mobility. There is little tendency to local heat on a migratory pattern, and no residual arthritic or other chronic organic joint changes have been described. GASTROINTESTINAL. Symptoms and signs referable to the gastrointestinal tract are variable in severity, but careful observation of the stools for gross or occult blood commonly indicates some degree of hemorrhage. Various authors list gastrointestinal symptoms in 50 to 80 per cent of children with anaphylactoid purpura.2, 6, 12 In typical patients there are episodes of colicky abdominal pain, nausea, vomiting and occasionally hematemesis. These may be the presenting symptom, preceding skin and other lesions by a few hours to several days. The degree of gastrointestinal bleeding varies from inconsequential in most to occasional paticnts with massive hemorrhage requiring transfusion therapy. The bleeding site or sites may provide the nidus about which an intussusception forms. Although this complication occurs in only a small percentage of patients with anaphylactoid purpura, its seriousness makes it an important consideration. In contrast to the usual incidence of intussusception predominantly in the infant, the older patient with anaphylactoid purpura is the one more prone to intussusception. The finding of an acute condition of the abdomen due to intussusception in an older child should, therefore, alert the physician to the possibility of anaphylactoid purpura as the underlying disease. Areas of edema of the bowel wall have been demonstrated radiographically, not unlike those seen in regional ileitis. This may explain
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the tendency of these patients to irreducible intussusception and suggests that attempts at reduction by hydrostatic pressure are not appropriate. Although the question of local bowel edema (and hemorrhage) or intermittent intussusception as the cause of the colicky abdominal pain may be uncertain in a given patient, the discomfort is acute and often severe enough to encourage one to consider surgical intervention. URINARY FINDINGS. Hematuria associated with anaphylactoid purpura was first mentioned by Henoch in 18745 and re-emphasized by Gairdner6 in 1948. In subsequent years it has become increasingly obvious that the presence or absence of renal involvement is the most significant prognostic feature of the syndrome.2- 18 It occurs in 20 to 60 per cent of reported cases as judged by the presence of abnormal urinary findings (hematuria and proteinuria), but the severity of the findings varies widely from patient to patient. The clinical resemblance of the acute renal findings in anaphylactoid purpura to those of acute glomerulonephritis is close. Both show hematuria, proteinuria, elevated blood pressure, and at times an elevation of blood urea nitrogen and a reduction of serum albumin. By contrast, evidence for a preceding streptococcal infection in anaphylactoid purpura has not been demonstrated with sufficient frequency to be convincing, and in the typical cases of each, glomerular histologic changes are usually different (though in themselves not diagnostic. ) 3, 5, 17 Whereas chronic nephritis is uncommon after classic acute glomerulonephritis, it occurs in about 25 per cent of patients with anaphylactoid purpura nephritis. Of interest in this respect is the speculation of Wedgwood and Klaus 18 that the renal manifestations may occur in the absence of skin or visceral lesions, thus providing an inapparent source of chronic glomerulonephritis. In general, hematuria and proteinuria appear from a few days to weeks after the skin and other visceral manifestations. In none of the reported series has the nephritic component made its appearance after six weeks' duration of the patient's illness, and in the majority it appears within the first three weeks. We have noted, in a single patient, the presence of characteristic renal histologic changes more than a week before the appearance of proteinuria and hematuria. There seems to be a predilection for older children, this complication occurring in less than 25 per cent of infants and over 50 per cent of older children with anaphylactoid purpura. 2 Urinary findings also tend to be less severe and less prolonged in infants. Hypertension is limited to those patients with renal involvement and even in these occurs in only one in four. It is most often moderate in degree and transient in duration.
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Urinary findings may be recurrent or persistent, and in our experience and that of others these patients provide a significant source of chronic glomerulonephritis. We have observed5 that prolonged hypertension and marked proteinuria are likely to be accompanied by more serious and progressive renal histologic changes. In a few children the renal involvement may be rapidly progressive, and death may occur with renal failure in a period of months. Patients with massive proteinuria may exhibit a typical nephrotic syndrome of severe degree. RENAL HISTOLOGY. Wedgwood and Klaus 18 suggested that many of the cases of chronic nephritis, in which the etiology is obscure, may be the product of anaphylactoid nephritis in which the characteristic skin lesions either did not occur or were so mild as to be overlooked. This prompted us to perform percutaneous renal biopsies in patients with the clinical diagnosis of anaphylactoid purpura in the hope that a characteristic renal lesion might be found. 5 It was noted that in the majority of these patients the glomerular involvement tended to be focal and that the severity of the lesion varied from one glomerulus to another. This is essentially the same histopathologic lesion as reported by other investigators.3 • 17 Thus, given a patient with persistent urinary abnormalities and these particular histopathologic changes in the kidney, the likelihood seems good that the etiology is anaphylactoid purpura. We hasten to add, however, that these changes closely resemble those seen in the kidney in disseminated lupus erythematosus and that in an occasional patient with known anaphylactoid purpura we have found the renal histopathologic changes to be diffuse and to resemble closely those of poststreptococcal acute glomerulonephritis. Terminally, the renal histology is indistinguishable from other forms of progressive renal failure. The mortality rate of approximately 2 per cent in anaphylactoid purpura is due almost entirely to renal failure. Laboratory Studies
There are no specific laboratory tests which are diagnostic of anaphylactoid purpura; however, a number are useful in differential diagnosis and in following the patient's course. Platelet counts are usually normal, or elevated if hemorrhage is significant. Serial examination of the stool for blood is desirable to detect patients with gastrointestinal involvement, while the hemoglobin and hematocrit values may call one's attention to inapparent blood loss. Serial urinalysis in the first six weeks should be a routine procedure if patients with renal involvement are to be detected. Tests designed to evaluate the bleeding and clotting mechanisms are uniformly within normal limits.
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Treatment
THE ANTIHISTAMINICS. The possibility that this disease might be influenced by the administration of antihistaminic preparations was investigated by Allen et aJ.2 in 37 patients, and they report that "we have not found this group of drugs to be of any benefit in the management of these patients." GLUCOCORTICOIDS. These compounds in a pharmacologic dose range (e.g. prednisone, 50 to 60 mg. per square meter or 1 to 3 mg. per kilogram daily) have been evaluated in the treatment of anaphylactoid purpura by a number of investigators.2 , 5, 14 The influence of cortisol and its derivatives on the course of the patient's illness varies widely, depending upon the sign or symptom under consideration. They have little effect on the total duration of the patient's illness, which usually averages four weeks, nor upon the tendency to recurrences. In fact, one group suggests that both duration and recurrences may be slightly increased in steroid-treated patients, though they admit that their findings may be more a reflection of the patients selected for treat· ment.14 Steroid therapy is often dramatically effective in relieving the pain and local swelling of the skin over the scalp and dorsum of the hands and feet. To some extent steroids seem to relieve joint discomfort, though the results are not consistent. Abdominal pain crises are often relieved by steroid therapy, and some believe that bowel edema and tendency to intussusception are reduced. The hemorrhagic skin lesions may be lessened during therapy, but recurrences have been noted in patients on adequate steroid doses, and it seems likely that these drugs have no value in management of the cutaneous hemorrhagic manifestations. The experiences of numerous investigators indicate that glucocorticoid therapy does not favorably influence the management of the nephritis of anaphylactoid purpura. CASE 1. V.V., an eight-year-old white girl, was in good health until two weeks before admission, when she had a low-grade fever and frontal headaches. All symptoms subsided after four days of symptomatic therapy with salicylates. Three days later she had a macular, reddish-pink rash over the distal portions of the legs which spread within the next 24 hours to involve the entire legs and buttocks. Coincident with the onset of the rash, a painful swelling of the right ankle was noted, and this progressed to involve the left ankle and both knees. In the next 24 hours she had anorexia, nausea, colicky abdominal pain and grossly bloody stools. The urine was not thought to be abnormal. Physical examination revealed a moderately ill child complaining of intermittent abdominal pain. A purpuric eruption was present over both legs and was most striking over the joints. The rash was reddish-purple and measured 2 to 4 mm. in diameter. Generalized abdominal tenderness was present. The blood pressure was normal, and no evidence of arthritis was present. The hemogram was within normal limits, the platelet count was 244,000, antistreptolysin 0 titer was les~ than 100 1,1nits, and a ~se in titer was not demonsrated. The
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Fig. 3. Purpuric skin lesions over the legs in patient V.Y. (Case 1). At onset these were erythematous macules.
Fig. 4. Photomicrograph (H & E stained) of a typical glomerulus in patient V.Y. (Case 1) show· ing moderate diffuse hypercellul· arity with focal accentuation.
stools showed evidence of blood on several occasions. Three urinalyses within the first two weeks revealed no abnormalities. Salicylates and codeine were not successful in relieving the abdominal pain, and after 48 hours she was started on small doses of prednisone with prompt clearing of symptoms over the next 24 hours. During the remainder of the week's hospitaliza· tion she experienced intermittent swelling of the joints of the leg and multiple remis· sions and exacerbations of the purpuric rash.
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A renal biopsy (Fig. 4) revealed generalized glomerular hypercellularity with focal accentuation. Endothelial proliferation and intimal swelling of the arterioles were significant. POLYARTERITIS NODOSA
Polyarteritis nodosa is a disease of unknown etiology included in the family of collagen or hypersensitivity disorders. 23 The diffuse involvement of arteries, arterioles and capillaries, supplying many different organs and tissue-systems, accounts for its protean clinical manifestations. The earlier used term "periarteritis" has been replaced by "polyarteritis" because all three layers of the arterial wall are involved. Typically20 there is fibrinoid necrosis, particularly of the media, and destruction of the intimal elastic tissue. All coats of the vessel wall become edematous and infiltrated with leukocytes, eosinophils being the most conspicuous cell form. Infiltration is followed by granuloma formation, fibroblastic proliferation and healing with fibrous tissue scarring. Thrombosis of the vessel, leading to infarction, recanalization and aneurysmal dilatation at points of bifurcation (which accounts for the term "nodosa") are common accompaniments. After a survey conducted by the Collagen Disease and Hypersensitivity Panel of the British Medical Research Council, Rose25 suggested that patients with polyarteritis be classified into two groups according to the presence or absence of lung involvement. Although other classifications19 • 27 of merit have been proposed, the classification of Rose stresses the peculiar importance of lung involvement in this disorder. "It is remarkable that lung lesions, if they occur at all, almost always precede lesions in other organs (sometimes by years) and are commonly associated with characteristic lesions in other organs not seen in cases without lung involvement."25 Similar cases have also been described as Wegener's granuloma, LoefHer's syndrome, Harkavy's syndrome, necrotizing granulomatosis and angiitis, diffuse eosinophilic arteritis and allergic granulomatosis. Polyarteritis Nodosa without Lung Involvement
This accounts for about two thirds of all cases and demonstrates a predominance in males up to 3: 1. Although this disorder may have its onset at any age, from infancy throughout life, increasing incidence occurs with advancing age. Winter is most often the season of onset. It is not infrequently preceded by a respiratory illness, either acute or chronic (including bronchiectasis, chronic bronchitis or suppurative otitis). The hemolytic streptococcus has frequently (up to 75 per cent) been identified in the preceding acute respiratory infections.
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A constitutional illness, with weight loss and fever, is prominent at some stage of the disease in nearly all patients. Anemia and leukocytosis are common, and about one third demonstrate a slight to moderate eosinophilia. Evaluation of serum proteins usually shows increased globulin and decreased albumin. The gastrointestinal tract is frequently involved by the polyarteritic process. The commonest symptom is poorly localized abdominal pain. Severe pain may occur early in the course. Hemorrhage is common and may at times be so severe as to necessitate surgery. Milder symptoms may include nausea, vomiting, diarrhea and constipation. Physical signs are usually slight or absent. At necropsy, submucous hemorrhages and superficial ulcers are frequent. The polyarteritic lesions are usually confined to the terminal branches of the mesenteric arteries. Although the liver may be involved in half of the cases, clinical evidence of liver dysfunction is infrequent. The spleen is only infrequently palpable, despite the fact that splenic polyarteritis has been reported to occur in up to 40 per cent of cases from which sections were available. Focal indurated skin lesions, probably all due to local polyarteritis, occur in about one fourth of the patients. These range from superficial papules to crops of tender, erythematous, subcutaneous nodules (0.5 to 1.0 cm. in diameter). The lesions usually involve the arms or legs and may subsequently ulcerate. Later in the course, subcutane· ous hemorrhage, skin ulceration and even gangrene of fingers or toes may occur. Less frequently, the skin lesions include recurrent urticaria, angioneurotic edema, maculopapular eruptions, purpuric rashes, painful subcutaneous areas and (rarely) scleroderma. Muscle pain and tenderness are frequent and often the initial manifestation of the disease. Arthritis is not uncommon at some time during the course and may be the presenting manifestation. The presence of subcutaneous nodules is rare. The arthritic manifestations may be acute and transitory, and at times even migratory as in rheumatic fever, or more chronic, closely resembling a rheumatoid type. The most common clinical manifestations of cardiac involvement are tachycardia, congestive failure and cardiac enlargement. Although cardiac pain is uncommon, necropsy often reveals infarcts (usually microscopic) and evidence of coronary polyarteritis (about 50 per cent). Pulmonary manifestations in this group are attributable to infection or heart failure. Retinal hemorrhage is a late finding and occurs in association with hypertension. Other less common ocular lesions include episcleritis, ulceration and iridocyclitis. Neurologic evaluation demonstrates abnormalities of peripheral motor and sensory nerves in about one third of the patients. Most commonly the signs are those of a widespread (but asymmetrical) periph-
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eral neuritis; however, the lesion may involve only isolated nerve trunk. Evidence gained from histologic sections suggests that the peripheral nerve lesions are related to the local polyarteritis. Less common manifestations include convulsions, cranial nerve involvement and psychiatric disorders. Microscopic evidence of cerebral polyarteritis is rarely present, and lesions of the central nervous system are in most cases attributable to the hypertension or atheroma. Renal involvement occurs at some stage of the disease in about 80 per cent of the patients. The commonest lesion consists of the polyarteritic involvement only. This lesion is usually associated clinically with proteinuria and hematuria. Next most common is the occurrence of a characteristic form of glomerulitis, as described by Davison et aP1 Clinically, such cases demonstrate macroscopic or heavy microscopic hematuria and early renal failure. A combination of these two histologic lesions occurs least frequently. In considering the relation of hypertension to renal involvement, Rose25 concluded that the hypertension in most cases of polyarteritis is a sequel to the renal involvement (either polyarteritis or glomerulitis), but that it is not a feature of the initial phase, and that early progressive renal failure and death may antedate its appearance. The blood pressure rises during the healing or healed stages of the renal lesions, and, once initiated, the hypertension is rapidly progressive. Death, in two thirds of the patients without pulmonary involvement, is attributable to the renal lesion. In the remaining cases, demise is attributable, in the main, to coronary disease or severe gastroenteritis. Polyarteritis with Lung Involvement
This accounts for approximately one third of the cases and shows no sex predilection. Onset of systemic polyarteritis is almost invariably preceded by a respiratory illness. The duration of the preceding respiratory involvement is variable: usually less than one year, although in one quarter or more of the patients a long history (occasionally up to seven years) of respiratory infections may be elicited. That this phase of the illness is associated with the presence of specific pulmonary lesions is highly likely. A past history of rheumatic fever can be elicited in about one fifth of the patients. Clinically, the main symptoms are similar to those of asthma, pneumonia or chronic bronchitis. The asthma appears to be distinct from the usual allergic asthma in that absence of a positive family history is common, the symptoms begin at any age, it is associated with an extremely high eosinophilia, and, at necropsy, necrotizing lesions and polyarteritis of lung (and elsewhere) are usually present. The pneumonia may range in clinical severity from a transient, symptomless
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infiltration to large chronic abscesses unresponsive to antimicrobials. Hemolytic streptococci have been isolated from about one fourth of the cases. Radiologic examination shows a variable pattern of consolidation. The nose or middle ear may be occasionally involved with the typical granulomatous lesion. Severe lung changes are almost invariably present in those patients examined at necropsy. The most common (one half) lesion is the presence of nodular or caseous lesions, often resembling tuberculosis (but with absence of tubercle bacilli). Other lesions include hemorrhagic pneumonias, cavities, infarcts, fibrosis and bronchiectasis. When adequate sections have been available,25 microscopic examination has shown the characteristic necrotizing or granulomatous lesion to be present in about two thirds of the cases and pulmonary polyarteritis in about three quarters. Diffuse and focal eosinophilic infiltration was also frequently noted by these investigators. The incidence of polyarteritis in other organs and their accompanying clinical manifestations are in the main similar to those in cases without lung involvement. Hypertension occurs less frequently, and this appears to be related to the shorter survival time of subjects with lung involvement once systemic polyarteritis becomes established. In the alimentary tract, superficial ulcerations (at all levels, from mouth to colon) are more extensive and frequent. At necropsy, granulomatous lesions involving liver, kidney, spleen, lymph nodes and heart have been noted, as well as a widespread diffuse and focal eosinophilic infiltration of interstitial tissues in those in whom a high blood eosinophilia was present at the time of death. The mean total duration of the disease is longer in patients with pulmonary involvement as compared to those in whom the lungs are spared. The period of survival when dated from the onset of systemic polyarteritis, however, is less in those with pulmonary involvement. Death is attributable to the various forms of pulmonary disease in slightly less than one half of the cases and to the renal involvement in about one fourth of the cases. Polyarteritis Nodosa in the First Year of Life
Reference to the literature22 , 26 shows reports of about 20 cases of polyarteritis nodosa occurring under the age of one year. It proved to be fatal in all but two. Clinically, most of the patients had rash, pyrexia, upper respiratory tract manifestations and progressive cardiac failure or sudden death. In most, at necropsy, typical polyarteritic lesions were found to involve the skin, upper respiratory tract and heart, the maximal lesions involving the coronary arteries.
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Response to Corticoid Therapy
In May, 1960, the Collagen Disease and Hypersensitivity Panel24 of the British Medical Research Council reported on a survey involving 21 cases of histologically proved polyarteritis, treated with cortisone and followed up for three to five years. These cases were then compared with a series of untreated cases surveyed previously. At 12 months the results in the treated group are distinctly superior, although the difference between the two groups is reduced if patients entering the trial with hypertension are excluded. At three years the advantage enjoyed by the treated group has diminished and disappears entirely if patients with initial hypertension are excluded. By four years, although the numbers for comparison had fallen, the percentage of survival in the two groups is the same. Exclusion of the hypertensive patients, at this point, reveals a bias in favor of the untreated group, among whom no further deaths had taken place after the first year of disease. In view of the differences between treated and untreated groups, it is probably safer to avoid further comparison. The start of treatment certainly brought speedy and often dramatic improvement to most patients. On the other hand, it later brought distressing, unpleasant complications to a few. The trial has not produced evidence that cortisone, in the dosages given * in these patients, improved the chances of ultimate recovery; possibly it postponed death. CASE 2. T.H., a 12-year-old colored boy, was in good health until the onset of acute swelling and pain on the left side of his face. Four days later, because the swelling and pain were more severe and he had become febrile, he consulted a physician, who found an elevated temperature and gave the patient penicillin, streptomycin and demethylchlortetracyc1ine. Further progression of the symptoms, plus anorexia and malaise, necessitated hospitalization the following day. The left facial involvement subsided in a few days, only to be followed by similar involvement of the right side of the face. Over the next two weeks he had tender, hot, swollen and erythematous elbows; lower left-sided chest pain and tenderness; tender, hot, erythematous swelling of the feet and ankles (greater on the left); sloughing of skin between toes, fingers and over the elbows; bilateral knee and calf tenderness; bilateral postauricular and auricular swelling; periumbilical cramping pain; tenderness with pain on motion of the cervical and thoracic vertebrae; and a generalized, progressive, nodular erythematous eruption, particularly involving the face, arms and legs. Fever persisted despite massive antimicrobial therapy. The patient was said to have had rheumatic fever at the age of six years, though the basis for this diagnosis was uncertain in the parent's mind. On admission here the patient was noted to have pain with movement of all joints, plus periorbital edema and facial asymmetry (right side swollen). His temperature was 102 F., blood pressure 120/70, pulse 130 and respirations 30. There were denuded areas on the fingers and elbows. Firm, tender, erythematous nodules (0.5 to 1 cm. in diameter) were present over the arms and legs. The liver was palpable 4 cm. below the right costal margin and was tender. The extremities were tender to touch, particularly the calf, and muscular weakness was generalized. No definite peripheral or cranial nerve involvement was noted. ,. The numbers for comparison are small, but suggest that patients on higher doses of steroids fared better than the untreated group. 0
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Fig. 5. Photomicrograph (H & E stained) of a representative glomerulus in patient T.H. (Case 2) showing moderate diffuse hypercellularity. Hemoglobin was 6.4 gm. per 100 mI., and hematocrit 20 volumes per cent. The white blood cell count was 22,500 with 94 per cent neutrophils. A trace of proteinuria was noted, and the urine specific gravity was above 1.020. Febrile agglutination and multiple skin tests were negative. Antistreptolysin a titers on admission and three weeks later were 1250 Todd units. Numerous blood cultures were negative. Total serum protein was 5.7 gm. per 100 mI., and electrophoresis revealed the albumin to be 1.24 gm. and gamma globulin to be 2.33 gm. SGOT was 95 and SGPT 80. Examination of cerebral spinal fluid showed no cells, negative culture, and normal chemistries. Direct Coombs test result was negative, and no LE cells were seen on numerous examinations. Bone marrow examination showed an increase in mature plasma cells, some of which were binucleated and trinucleated. Skin-muscle biopsy showed a necrotizing polyarteritis, with thrombi and infiltration by histiocytes, polymorphonuclear leukocytes, plasma cells and lymphocytes. Percutaneous renal biopsy revealed medial proliferation and fibrinoid degeneration of the single arteriole seen. The glomeruli showed varying degrees of proliferative change (Fig. 5). On corticosteroid therapy, in full therapeutic dosage (e.g. 50 mg. of prednisone per square meter daily), the patient had a remission of the abnormal clinical and laboratory findings. After several months the dosage was gradually reduced to one 5-mg. tablet of prednisone four times a day, which maintained his asymptomatic state. The glucocorticoids were completely discontinued after eight months, and the patient is still asymptomatic some 13 months later. CASE 3. G.C. was a 13 7/IZ-year-old Latin American girl who had been in good health until two months before admission, when she suffered daily frontal headaches and nonprojectile, blood-streaked vomitus. Two weeks later she experienced hemoptysis and was told by her local physician that she had a "spot in her lungs" and that her stools and urine contained blood. She was found to be anemic, and two transfusions were administered.
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All symptoms continued and increased in severity until the day before admission here, when she had spontaneous epistaxis. There was no history of abdominal pain, arthralgia, fever or skin rash. Physical examination revealed a pale, chronically ill child with depression of the sensorium. Her blood pressure was normal. The remainder of the examination was normal. Laboratory studies revealed the following: hemoglobin 7.5 gm. per 100 ml., hemato· crit 19 volumes per cent, blood urea nitrogen 130 mg.; sodium 144 mEq. per liter, potassium 3.S mEq., phosphorus 7.5 mg.; antistreptolysin 0 titer 625 Todd units; and LE preparations negative on six occasions. The urine contained protein and numerous red blood cells. A study of her coagulation mechanism indicated no abnormalities. A roentgenogram of the chest revealed a questionable, but consistent, area of density in the right apex suggestive of a granulomatous lesion. The glomerular filtration rate was 5.0 cc. per minute per square meter (normal 60 to SO cc. per minute), and the effective renal plasma flow was 22 cc. per minute per square meter (normal 300 to 350 cc. per minute). After admission she was given a transfusion and her general condition transiently improved. She continued to have both hemoptysis and hematemesis, however, and her urine and stools continued to reveal active bleeding. On only one occasion did she show evidence of bleeding in other areas, and this was subconjunctival hemorrhage associated with a period of severe vomiting. Her blood pressure became elevated during the third week of hospitalization, and attempts to control it were not successful. She continued to have progression of her symptoms with evidence of pneumonitis, peripheral edema, weakness and disturbed sensorium, and expired during the sixth week of hospitalization. Findings at necropsy were those of typical extensive polyarteritis of the pulmonary involvement type as described in the text. PURPURA FULMINANS
Purpura fulminans is a rare syndrome characterized by the sudden onset of large, scattered, often symmetrically placed, ecchymotic areas principally over the legs. 28- 32 In typical patients there is rapid progression of the lesion resulting in extensive involvement of the extremities and frequently culminating in gangrene. The mortality rate is exceedingly high. 28 The disease is usually preceded by an upper respiratory tract infection of mild to moderate severity. Scarlet fever has been noted to precede the onset in 30 to 50 per cent of the reported cases, and evidence of nonerythrodermic streptococcal infection is frequently present.29 Several cases have had their onset following typical varicella. After a latent period varying between three and 30 days there is the sudden onset of ecchymotic lesions, which are initially confined to the distal portions of the legs, but spread rapidly and within a few hours may involve large areas of the extremities and trunk. The lesions are usually bluish-red with well demarcated, slightly elevated borders, and large subepidermal bullae containing a reddish-clear fluid are present in the central portions. As the ecchymotic areas progress they become confluent, and their color changes to a bluish-black. Coincident with this is the development of a brawny edema and disappearance of the arterial pulse distal to the lesion.
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Severe abdominal pain, vomiting, fever, hematochezia, oliguria, gross hematuria and peripheral vascular collapse are frequently observed. In the majority of reported cases abnormalities in coagulation have been noted. 29- 31 Most authors have noted a moderate increase in the coagulation time and a moderate reduction in circulating platelets. The prothrombin time is characteristically increased, and deficiencies of both factor V and fibrinogen have been described. 29 ,30 One recent report describes an increase in the antithrombin III factor. 31 Histologically, the involved areas reveal massive coagulation necrosis of the skin, subcutaneous tissue and skeletal muscle. Extensive microthromboses of the hyaline or fibrinoid type occlude the majority of the arteries and veins. The arterial walls generally reveal focal fibrinoid necrosis. Renal cortical necrosis has also been observed, as has occlusion of the renal artery by hyaline thrombi. Although this disease is thought to represent a hypersensitivity response, its precise relation to anaphylactoid purpura and polyarteritis is uncertain. Histologically, the lesion resembles that of thrombotic thrombocytopenic purpura, and the fulminant picture plus the occasional renal cortical necrosis suggests a relation to the generalized Shwartzman phenomenon. CASE 4. D.T., an eight-year-old white boy, was well until two weeks before admission, when he had an acute upper respiratory tract infection associated with a lowgrade fever and cough. All symptoms subsided after four days, and he remained well until seven days later, when there was the acute onset of penile and scrotal edema. Antihistaminics produced some relief. Two days later he experienced painless hematuria and noted the appearance of an erythematous, macular area on the anterior surface of both legs. There was rapid extension of these lesions within 24 hours with
Fig. 6. Photograph of lesions in D.T. (Case 4) on the day after admission, demonstrating circumscribed ecchymotic lesions with red periphery and central bullous formation.
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Fig. 7. Photograph of patient D.T. (Case 4) 14 days later, demonstrating residual bullae and "dry" gangrene. the development of bullae. Additional erythematous lesions appeared on both proximal extremities, the lower part of the back, the axillae, and around one eye. Physical examination revealed a healthy-appearing white boy in no distress. Over the anterior and lateral surfaces of both legs there were large, well circumscribed, ecchymotic lesions with a bright red, raised periphery and central bullous formation filled with serosanguineous fluid. Additional ecchymotic lesions were located on both heels, both upper thighs, the lower sacral area, the left elbow and the left axilla. No petechial and no mucous membrane lesions were present. A brawny edema was present over the right distal extremity, and the peripheral pulses in this extremity were absent. The blood pressure was normal. Significant laboratory studies revealed the following: hemoglobin 8.2 gm. per 100 ml.; white blood cell count 18,300, with a shift to the left; platelet count 107,000, reticulocytes 2.6 per cent; urine grossly bloody; direct and indirect Coombs test results negative; stools positive for occult blood; total serum proteins 7.3 gm. per 100 ml., with an elevated gamma globulin level (2.0 gm. per 100 mI.); antistreptolysin a titer 500 Todd units. The prothrombin time was greatly prolonged, and although clotting was essentially normal, there was rapid dissolution of the clot within one hour. Other clotting factors were essentially normal with the exception of fibrinogen, which was 89 mg. per 100 ml. The child was immediately begun on massive antibiotic therapy and intravenous administration of hydrocortisone. The lesion on the right leg progressed rapidly to involve the entire lower leg and foot within 24 hours. There was a drop in hemoglobin level necessitating several transfusions. Brisk bleeding from the gastrointestinal and genitourinary tracts continued for approximately one week. There was gradual improvement of all ecchymotic areas except those of the right leg, which progressed to a "dry" gangrene. Three weeks after admission he began to pass multiple calcium phosphate stones, and x-ray films of the abdomen revealed bilateral staghorn calculi. Amputation of the right leg was performed after five weeks, and steroids were gradually discontinued without recurrence of symptoms. Histologic specimens revealed necrosis of the blood vessels and complete occlusion of both anterior and posterior tibial arteries by organizing thrombi. There were no significant changes in the walls of these vessels. The patient has continued to do well. The renal lithiasis appears, by exclusion, to be related to his prolonged bed rest.
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REFERENCES Anaphylactoid Purpura 1. Alexander, H. L., and Eyermann, C. H.: Food Allergy in Henoch's Purpura. Arch. Dermat. 6 Syph., 16:322, 1927. 2. Allen, D. M., Diamond, L. K, and Howell, D. A.: Anaphylactoid Purpura in Children (SchOnlein·Henoch Syndrome). Am. J. Dis. Child., 99:833, 1960. 3. Bergstrand, A., Bergstrand, C. G., and Bucht, H.: Kidney Lesions Associated with Anaphylactoid Purpura in Children. Acta Pediat., 49:57, 1960. 4. Derham, R. J., and Rogerson, M. M.: The Sch1inlein·Henoch Syndrome, with Particular Reference to Renal Sequelae. Arch. Dis. Childhood, 31: 364, 1956. 5. Dodge, W. F., Daeschner, C. W., Brennan, J. C., Rosenberg, H. S., Travis, L. B., and Hopps, H. C.: Percutaneous Renal Biopsy in Children. II. Acute Glomeru· lonephritis, Chronic Glomerulonephritis, and Nephritis of Anaphylactoid Purpura. Pediatrics, 30:297, 1962. 6. Gairdner, D.: The Sch1inlein-Henoch Syndrome (Anaphylactoid Purpura). Quart. J. Med., 17:95, 1948. 7. Komrower, G.: Discussion of T. K Oliver and H. L. Barnett. 1o A.M.A. J. Dis. Child., 90:546,1955. 8. Levitt, L. M., and Burbank, B.: Glomerulonephritis as a Complication of the SchOnlein-Henoch Syndrome. New England J. Med., 248:530, 1953. 9. Lewis, I. C.: The SchOnlein-Henoch Syndrome (Anaphylactoid Purpura) Com· pared with Certain Features of Nephritis and Rheumatism. Arch. Dis. Child· hood, 30:212, 1955. 10. Oliver, T. K, and Barnett, H. L.: The Incidence and Prognosis of Nephritis Associated with Anaphylactoid Purpura (SchOnlein-Henoch Syndrome) in Chilo dren. A.M.A. J. Dis. Child., 90:544, 1955. 11. Osler, W.: The Visceral Lesions of Purpura and Allied Conditions. Brit. M.J., 1:517, 1914. 12. Panos, T. C.: Anaphylactoid Purpura in Children; in Mesenchymal Diseases in Childhood. 21st Pediatric Research Conference, Ross Laboratories, 1957, pp. 88-92. 13. Philpott, M. G.: The SchOnlein-Henoch Syndrome in Childhood, with Particular Reference to the Occurrence of Nephritis. Arch. Dis. Childhood, 27:480, 1952. 14. Philpott, M. G., and Briggs, J. N.: Treatment of the SchOnlein-Henoch Syndrome with A.C.T.H. and Cortisone. Arch. Dis. Childhood, 28:57, 1953. 15. Rubin, M. 1.: Discussion of paper by Oliver et al. Am. J. Dis. Child., 90:545, 1955. 16. Starky, G., and Thileu, A.: A Study on the Onset and Prognosis of Acute Vascular Purpura (the Sch1inlein-Henoch Syndrome) in Children. Acta Pediat., 49:217,1960. 17. Vernier, R. L., Worthen, H. G., Peterson, R. D., Colle, E., and Good, R. A.: Anaphylactoid Purpura. I. Pathology of the Skin and Kidney and Frequency of Streptococcal Infection. Pediatrics, 27:181, 1961. 18. Wedgwood, R. J. P., and Klaus, M. H.: Anaphylactoid Purpura (Sch1inleinHenoch Syndrome). A Long Term Follow-up Study with Special Reference to the Renal Lesion. Pediatrics, 16:196, 1955. Polyarteritis Nodosa 19. Black, R. L.: Polyarteritis Nodosa. Postgrad. Med., 31:426, 1962. 20. Idem: The Characterization of Polyarteritis Nodosa, Dermatomyositis and Pro· gressive Systemic Sclerosis. M. Clin. N. Amer., 45:1295, 1961. 21. Davison, J., Ball, J., and Platt, R.: The Kidney in Periarteritis Nodosa. Quart. J. Med., 17:175, 1948. 22. Henry, M. J., Stoeckle, H. G., and Hopps, H. C.: Periarteritis in a 4-Month-Old Infant Unresponsive to Penicillinase. Am. Heart J., 60:817, 1960. 23. Moore, R. H., and Movat, H. Z. The Significance of Plasma Cells in the Lesions of Acute Polyarteritis. J. Path. 6 Bact. (London), 75:127,1958.
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24. Treatment of Polyarteritis Nodosa with Cortisone: Results after Three Years. Report to the Medical Research Council by the Collagen Disease and Hyper· sensitivity Panel. Brit. M.f., 5183,1399, 1960. 25. Rose, G.A.: Natural History of Polyarteritis. Brit. M.J., 2:1148, 1957. 26. Savage, T. R., and Smith, J. F.: Polyarteritis Nodosa and Congenital Pyloric Hy· pertrophy in a 3·Month·Old Infant. J. Clin. Path., 13:291, 1960. 27. Zeek, P. M.: Periarteritis Nodosa and Other Forms of Necrotizing Angiitis. New England J. Med., 248:764, 1953. Purpura Fulminans
28. Crawford, S. E., and Riddler, J. G.: Purpura Fulminans. Am. J. Dis. Child., 97: 198, 1959. 29. Dyggve, H.: A Case of Purpura Fulminans with Fibrinogenopenia in Association with Scarlatina. Acta Med. Scand., 127:382, 1947. 30. Feldman, R., Lubby, A. L., and Sala, A. M.: Purpura Fulminans, Thrombotic Thrombocytopenic Purpura and the Shwartzman Phenomenon. Am. J. Dis. Child., 100:587, 1960. 3l. McKay, G. F., Pisciotta, A. V., and Johnson, S. A.: Homeostatic Mechanisms, Antithromin and Purpura Fulminans. Am. J. Clin. Path., 38:357, 1962. 32. Turin, R. D., Mandel, S., and Hornstein, L.: Fulminating Purpura with Gangrene of Lower Extremity Necessitating Amputation. J. Pediat., 54:206, 1959. University of Texas Medical Branch Galveston, Texas
As experience with the collagen diseases increases, one is frequently impressed by the lack of consistent definitions between them and the consequent difficulty in assigning a specific diagnosis to the patient's problem. Although anaphylactoid purpura, purpura fulminans and polyarteritis nodosa are usually considered to be separate entities, they may have several clinical manifestations in common. For example, anaphylactoid purpura and purpura fulminans characteristically present with an erythematous and sometimes purpuric skin rash involving principally the legs; all three syndromes are likely to be found in the wake of acute infectious processes; and each may demonstrate articular, visceral and renal involvement. The histologic changes in all are characterized by a perivasculitis varying from an infiltrative process with local hemorrhage in anaphylactoid purpura to a gangrenous process in some patients with purpura fulminans and polyarteritis nodosa. These and other considerations to be mentioned later seem to justify including the three syndromes in the same discussion. ANAPHYLACTOID PURPURA
This disease has been known by an unusually wide variety of synonyms: purpura rheumatica, Schoenlein's purpura, Henoch's purpura, From the Division of Renology and Metabolism, the Department of Pediatrics, University of Texas Medical Center, Galveston.
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nonthrombopenic purpura, Osler's syndrome, primary purpura, allergic purpura, vascular anaphylactoid purpura, acute vascular purpura, Schoenlein-Henoch syndrome and anaphylactoid purpura. Today, Henoch-Schoenlein syndrome and anaphylactoid purpura are the terms most commonly used. The clinical picture is characterized by nonthrombopenic purpura, most prominent over the lower part of the trunk, hips and legs, by crises of abdominal pain often associated with melena, by arthralgia, and by urinary findings resembling those of acute nephritis. Low-grade fever is common before the onset, but does not seem to be part of the clinical syndrome. These signs and symptoms may present in any order, and the severity of individual components may vary from absent to being the dominant feature of the patient's illness. Etiologic Factors
Although the etiology of anaphylactoid purpura, like that of other collagen diseases, is unknown, there are certain circumstantial factors which strongly suggest a hypersensitivity state. 6 , 9, 12, 17 In three large surveys of anaphylactoid purpura in childhood2, 12, 18 the age at onset was found to vary from six months to 16 years, with the peak risk between four and five years of age. There is a moderate preponderance of male patients in most reports. The syndrome is rare in the Negro, but this may represent diagnostic failure because of skin color or sampling error in hospitals serving predominantly white patients.2, 18 There seems to be a definite seasonal incidence, fall and spring periods showing the peak number of admissions. 2, 13 Many substances and conditions have been suspected as etiologic factors. These children tend to have a history of major allergic conditions approximately twice that of the general population (14 versus 7 per cent).2 Studies of the family allergic history have been disappointing. Alexander and Eyermann1 were the first to establish food allergies and included milk, egg, chocolate and beans as possibly significant. Various medications, particularly aspirin and the antimicrobials, have been reported as causative agents. In one of our own patients the onset of symptoms followed an injection of penicillin G, and in this subject a significant titer of penicillin antibodies was demonstrated (agar gel diffusion technique). Studies of the patient's family history are usually unrewarding,2 though isolated reports of rheumatic fever, rheumatoid arthritis and anaphylactoid purpura in other members have been noted. In this respect the presence of the nephrotic syndrome, documented milk allergy, and severe asthma, respectively, in the three siblings of one of our patients seems more than coincidental.
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History of a recent acute infectious process can be found in approximately two thirds of patients with anaphylactoid purpura. Although beta hemolytic streptococcal infections have been suspected on the basis of circumstantial evidence, studies of patients have failed to show serologic evidence of significant degree. For example, Komrower7 in England found an increased incidence of rheumatic fever, acute glomerular nephritis and anaphylactoid purpura during an epidemic of beta streptococcal infections during 1953-54. Rubin15 reports that 70 per cent of his patients had beta streptococci in throat culture at the time of admission, while Starky16 found only 34 per cent and states that only 3 per cent of his 103 patients had significant increase in antistreptolysin 0 titer. Vernier17 and associates studied this problem and concluded that the incidence of increased (33 per cent) antistreptolysin 0 titer in their 39 patients was not higher than that which would be found in patients with nonstreptococcal illness. Although it seems unlikely that the streptococcus is the principal etiologic factor, its role is yet to be clearly defined. The 90 per cent incidence of some acute infectious process preceding the onset of anaphylactoid purpura in children strongly suggests that they play an inciting, if not etiologic, role. Clinical Manifestations
SKIN AND SUBCUTANEOUS TISSUES. The characteristic skin involvement is at present essential to the diagnosis (see Fig. 3). The skin lesions are most often urticarial at onset, then fade into erythematous macules or papules, often developing a pinhead-sized hemorrhagic center or progressing to "bruiselike" ecchymoses 1 to 4 cm. in diameter. The sites of predilection are the feet, ankles, legs, buttocks and lower part of the trunk, while lesions above the waist and on the arms are uncommon. This distribution suggests reduced vascular integrity and also helps to distinguish anaphylactoid purpura from the thrombopenic purpuras. Rare examples are described in which the purpuric skin lesion progresses to cutaneous necrosis or even a gangrenous extremity,32 but in the present author's opinion these cases are more properly classified as purpura fulminans. The purpuric and other cutaneous manifestations may precede or follow the other clinical findings and are occasionally so mild that they are not recognized. Several authors suggest that skin lesions may indeed be entirely absent, thus making accurate diagnosis difficult and hazardous. In typical patients the urticarial phase is transient, and purpura continues for only a few weeks, but in some patients the purpura may be recurrent or persistent over a period of years. Coincident in time, but separate in location, are the areas of painful,
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brawny, local edema which occur in over half of patients· with anaphylactoid purpura,2 principally in subjects under three years of age. This manifestation shows a predilection for the dorsum of the hands, feet and scalp and is sometimes quite painful. It may be perplexing unless recognized as part of the anaphylactoid purpura syndrome. Recurrence of the rash is not uncommon, whereas recurrence of the painful local areas of edema is rare. Histologically, Vernier and others17 have shown that the hemorrhagic skin lesion is characterized by perivascular infiltrations about the small blood vessels of the dermis with plugging of some vessels by leukocyte-platelet thrombi. JOINTS. Periarticular pain, tenderness or swelling is the second most common finding, being present in approximately two thirds of the patients.2 The joints most often involved are the ankle and knee, less frequently the wrist and fingers. There seems to be a tendency for more prominent skin lesions in the involved articular areas. The joint symptoms may resemble those of acute articular involvement in lupus erythematosus, rheumatic fever or rheumatoid arthritis. They vary in severity from periarticular pain without objective findings to acute local swelling, tenderness and reduction of joint mobility. There is little tendency to local heat on a migratory pattern, and no residual arthritic or other chronic organic joint changes have been described. GASTROINTESTINAL. Symptoms and signs referable to the gastrointestinal tract are variable in severity, but careful observation of the stools for gross or occult blood commonly indicates some degree of hemorrhage. Various authors list gastrointestinal symptoms in 50 to 80 per cent of children with anaphylactoid purpura.2, 6, 12 In typical patients there are episodes of colicky abdominal pain, nausea, vomiting and occasionally hematemesis. These may be the presenting symptom, preceding skin and other lesions by a few hours to several days. The degree of gastrointestinal bleeding varies from inconsequential in most to occasional paticnts with massive hemorrhage requiring transfusion therapy. The bleeding site or sites may provide the nidus about which an intussusception forms. Although this complication occurs in only a small percentage of patients with anaphylactoid purpura, its seriousness makes it an important consideration. In contrast to the usual incidence of intussusception predominantly in the infant, the older patient with anaphylactoid purpura is the one more prone to intussusception. The finding of an acute condition of the abdomen due to intussusception in an older child should, therefore, alert the physician to the possibility of anaphylactoid purpura as the underlying disease. Areas of edema of the bowel wall have been demonstrated radiographically, not unlike those seen in regional ileitis. This may explain
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the tendency of these patients to irreducible intussusception and suggests that attempts at reduction by hydrostatic pressure are not appropriate. Although the question of local bowel edema (and hemorrhage) or intermittent intussusception as the cause of the colicky abdominal pain may be uncertain in a given patient, the discomfort is acute and often severe enough to encourage one to consider surgical intervention. URINARY FINDINGS. Hematuria associated with anaphylactoid purpura was first mentioned by Henoch in 18745 and re-emphasized by Gairdner6 in 1948. In subsequent years it has become increasingly obvious that the presence or absence of renal involvement is the most significant prognostic feature of the syndrome.2- 18 It occurs in 20 to 60 per cent of reported cases as judged by the presence of abnormal urinary findings (hematuria and proteinuria), but the severity of the findings varies widely from patient to patient. The clinical resemblance of the acute renal findings in anaphylactoid purpura to those of acute glomerulonephritis is close. Both show hematuria, proteinuria, elevated blood pressure, and at times an elevation of blood urea nitrogen and a reduction of serum albumin. By contrast, evidence for a preceding streptococcal infection in anaphylactoid purpura has not been demonstrated with sufficient frequency to be convincing, and in the typical cases of each, glomerular histologic changes are usually different (though in themselves not diagnostic. ) 3, 5, 17 Whereas chronic nephritis is uncommon after classic acute glomerulonephritis, it occurs in about 25 per cent of patients with anaphylactoid purpura nephritis. Of interest in this respect is the speculation of Wedgwood and Klaus 18 that the renal manifestations may occur in the absence of skin or visceral lesions, thus providing an inapparent source of chronic glomerulonephritis. In general, hematuria and proteinuria appear from a few days to weeks after the skin and other visceral manifestations. In none of the reported series has the nephritic component made its appearance after six weeks' duration of the patient's illness, and in the majority it appears within the first three weeks. We have noted, in a single patient, the presence of characteristic renal histologic changes more than a week before the appearance of proteinuria and hematuria. There seems to be a predilection for older children, this complication occurring in less than 25 per cent of infants and over 50 per cent of older children with anaphylactoid purpura. 2 Urinary findings also tend to be less severe and less prolonged in infants. Hypertension is limited to those patients with renal involvement and even in these occurs in only one in four. It is most often moderate in degree and transient in duration.
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Urinary findings may be recurrent or persistent, and in our experience and that of others these patients provide a significant source of chronic glomerulonephritis. We have observed5 that prolonged hypertension and marked proteinuria are likely to be accompanied by more serious and progressive renal histologic changes. In a few children the renal involvement may be rapidly progressive, and death may occur with renal failure in a period of months. Patients with massive proteinuria may exhibit a typical nephrotic syndrome of severe degree. RENAL HISTOLOGY. Wedgwood and Klaus 18 suggested that many of the cases of chronic nephritis, in which the etiology is obscure, may be the product of anaphylactoid nephritis in which the characteristic skin lesions either did not occur or were so mild as to be overlooked. This prompted us to perform percutaneous renal biopsies in patients with the clinical diagnosis of anaphylactoid purpura in the hope that a characteristic renal lesion might be found. 5 It was noted that in the majority of these patients the glomerular involvement tended to be focal and that the severity of the lesion varied from one glomerulus to another. This is essentially the same histopathologic lesion as reported by other investigators.3 • 17 Thus, given a patient with persistent urinary abnormalities and these particular histopathologic changes in the kidney, the likelihood seems good that the etiology is anaphylactoid purpura. We hasten to add, however, that these changes closely resemble those seen in the kidney in disseminated lupus erythematosus and that in an occasional patient with known anaphylactoid purpura we have found the renal histopathologic changes to be diffuse and to resemble closely those of poststreptococcal acute glomerulonephritis. Terminally, the renal histology is indistinguishable from other forms of progressive renal failure. The mortality rate of approximately 2 per cent in anaphylactoid purpura is due almost entirely to renal failure. Laboratory Studies
There are no specific laboratory tests which are diagnostic of anaphylactoid purpura; however, a number are useful in differential diagnosis and in following the patient's course. Platelet counts are usually normal, or elevated if hemorrhage is significant. Serial examination of the stool for blood is desirable to detect patients with gastrointestinal involvement, while the hemoglobin and hematocrit values may call one's attention to inapparent blood loss. Serial urinalysis in the first six weeks should be a routine procedure if patients with renal involvement are to be detected. Tests designed to evaluate the bleeding and clotting mechanisms are uniformly within normal limits.
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Treatment
THE ANTIHISTAMINICS. The possibility that this disease might be influenced by the administration of antihistaminic preparations was investigated by Allen et aJ.2 in 37 patients, and they report that "we have not found this group of drugs to be of any benefit in the management of these patients." GLUCOCORTICOIDS. These compounds in a pharmacologic dose range (e.g. prednisone, 50 to 60 mg. per square meter or 1 to 3 mg. per kilogram daily) have been evaluated in the treatment of anaphylactoid purpura by a number of investigators.2 , 5, 14 The influence of cortisol and its derivatives on the course of the patient's illness varies widely, depending upon the sign or symptom under consideration. They have little effect on the total duration of the patient's illness, which usually averages four weeks, nor upon the tendency to recurrences. In fact, one group suggests that both duration and recurrences may be slightly increased in steroid-treated patients, though they admit that their findings may be more a reflection of the patients selected for treat· ment.14 Steroid therapy is often dramatically effective in relieving the pain and local swelling of the skin over the scalp and dorsum of the hands and feet. To some extent steroids seem to relieve joint discomfort, though the results are not consistent. Abdominal pain crises are often relieved by steroid therapy, and some believe that bowel edema and tendency to intussusception are reduced. The hemorrhagic skin lesions may be lessened during therapy, but recurrences have been noted in patients on adequate steroid doses, and it seems likely that these drugs have no value in management of the cutaneous hemorrhagic manifestations. The experiences of numerous investigators indicate that glucocorticoid therapy does not favorably influence the management of the nephritis of anaphylactoid purpura. CASE 1. V.V., an eight-year-old white girl, was in good health until two weeks before admission, when she had a low-grade fever and frontal headaches. All symptoms subsided after four days of symptomatic therapy with salicylates. Three days later she had a macular, reddish-pink rash over the distal portions of the legs which spread within the next 24 hours to involve the entire legs and buttocks. Coincident with the onset of the rash, a painful swelling of the right ankle was noted, and this progressed to involve the left ankle and both knees. In the next 24 hours she had anorexia, nausea, colicky abdominal pain and grossly bloody stools. The urine was not thought to be abnormal. Physical examination revealed a moderately ill child complaining of intermittent abdominal pain. A purpuric eruption was present over both legs and was most striking over the joints. The rash was reddish-purple and measured 2 to 4 mm. in diameter. Generalized abdominal tenderness was present. The blood pressure was normal, and no evidence of arthritis was present. The hemogram was within normal limits, the platelet count was 244,000, antistreptolysin 0 titer was les~ than 100 1,1nits, and a ~se in titer was not demonsrated. The
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Fig. 3. Purpuric skin lesions over the legs in patient V.Y. (Case 1). At onset these were erythematous macules.
Fig. 4. Photomicrograph (H & E stained) of a typical glomerulus in patient V.Y. (Case 1) show· ing moderate diffuse hypercellul· arity with focal accentuation.
stools showed evidence of blood on several occasions. Three urinalyses within the first two weeks revealed no abnormalities. Salicylates and codeine were not successful in relieving the abdominal pain, and after 48 hours she was started on small doses of prednisone with prompt clearing of symptoms over the next 24 hours. During the remainder of the week's hospitaliza· tion she experienced intermittent swelling of the joints of the leg and multiple remis· sions and exacerbations of the purpuric rash.
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A renal biopsy (Fig. 4) revealed generalized glomerular hypercellularity with focal accentuation. Endothelial proliferation and intimal swelling of the arterioles were significant. POLYARTERITIS NODOSA
Polyarteritis nodosa is a disease of unknown etiology included in the family of collagen or hypersensitivity disorders. 23 The diffuse involvement of arteries, arterioles and capillaries, supplying many different organs and tissue-systems, accounts for its protean clinical manifestations. The earlier used term "periarteritis" has been replaced by "polyarteritis" because all three layers of the arterial wall are involved. Typically20 there is fibrinoid necrosis, particularly of the media, and destruction of the intimal elastic tissue. All coats of the vessel wall become edematous and infiltrated with leukocytes, eosinophils being the most conspicuous cell form. Infiltration is followed by granuloma formation, fibroblastic proliferation and healing with fibrous tissue scarring. Thrombosis of the vessel, leading to infarction, recanalization and aneurysmal dilatation at points of bifurcation (which accounts for the term "nodosa") are common accompaniments. After a survey conducted by the Collagen Disease and Hypersensitivity Panel of the British Medical Research Council, Rose25 suggested that patients with polyarteritis be classified into two groups according to the presence or absence of lung involvement. Although other classifications19 • 27 of merit have been proposed, the classification of Rose stresses the peculiar importance of lung involvement in this disorder. "It is remarkable that lung lesions, if they occur at all, almost always precede lesions in other organs (sometimes by years) and are commonly associated with characteristic lesions in other organs not seen in cases without lung involvement."25 Similar cases have also been described as Wegener's granuloma, LoefHer's syndrome, Harkavy's syndrome, necrotizing granulomatosis and angiitis, diffuse eosinophilic arteritis and allergic granulomatosis. Polyarteritis Nodosa without Lung Involvement
This accounts for about two thirds of all cases and demonstrates a predominance in males up to 3: 1. Although this disorder may have its onset at any age, from infancy throughout life, increasing incidence occurs with advancing age. Winter is most often the season of onset. It is not infrequently preceded by a respiratory illness, either acute or chronic (including bronchiectasis, chronic bronchitis or suppurative otitis). The hemolytic streptococcus has frequently (up to 75 per cent) been identified in the preceding acute respiratory infections.
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A constitutional illness, with weight loss and fever, is prominent at some stage of the disease in nearly all patients. Anemia and leukocytosis are common, and about one third demonstrate a slight to moderate eosinophilia. Evaluation of serum proteins usually shows increased globulin and decreased albumin. The gastrointestinal tract is frequently involved by the polyarteritic process. The commonest symptom is poorly localized abdominal pain. Severe pain may occur early in the course. Hemorrhage is common and may at times be so severe as to necessitate surgery. Milder symptoms may include nausea, vomiting, diarrhea and constipation. Physical signs are usually slight or absent. At necropsy, submucous hemorrhages and superficial ulcers are frequent. The polyarteritic lesions are usually confined to the terminal branches of the mesenteric arteries. Although the liver may be involved in half of the cases, clinical evidence of liver dysfunction is infrequent. The spleen is only infrequently palpable, despite the fact that splenic polyarteritis has been reported to occur in up to 40 per cent of cases from which sections were available. Focal indurated skin lesions, probably all due to local polyarteritis, occur in about one fourth of the patients. These range from superficial papules to crops of tender, erythematous, subcutaneous nodules (0.5 to 1.0 cm. in diameter). The lesions usually involve the arms or legs and may subsequently ulcerate. Later in the course, subcutane· ous hemorrhage, skin ulceration and even gangrene of fingers or toes may occur. Less frequently, the skin lesions include recurrent urticaria, angioneurotic edema, maculopapular eruptions, purpuric rashes, painful subcutaneous areas and (rarely) scleroderma. Muscle pain and tenderness are frequent and often the initial manifestation of the disease. Arthritis is not uncommon at some time during the course and may be the presenting manifestation. The presence of subcutaneous nodules is rare. The arthritic manifestations may be acute and transitory, and at times even migratory as in rheumatic fever, or more chronic, closely resembling a rheumatoid type. The most common clinical manifestations of cardiac involvement are tachycardia, congestive failure and cardiac enlargement. Although cardiac pain is uncommon, necropsy often reveals infarcts (usually microscopic) and evidence of coronary polyarteritis (about 50 per cent). Pulmonary manifestations in this group are attributable to infection or heart failure. Retinal hemorrhage is a late finding and occurs in association with hypertension. Other less common ocular lesions include episcleritis, ulceration and iridocyclitis. Neurologic evaluation demonstrates abnormalities of peripheral motor and sensory nerves in about one third of the patients. Most commonly the signs are those of a widespread (but asymmetrical) periph-
r
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eral neuritis; however, the lesion may involve only isolated nerve trunk. Evidence gained from histologic sections suggests that the peripheral nerve lesions are related to the local polyarteritis. Less common manifestations include convulsions, cranial nerve involvement and psychiatric disorders. Microscopic evidence of cerebral polyarteritis is rarely present, and lesions of the central nervous system are in most cases attributable to the hypertension or atheroma. Renal involvement occurs at some stage of the disease in about 80 per cent of the patients. The commonest lesion consists of the polyarteritic involvement only. This lesion is usually associated clinically with proteinuria and hematuria. Next most common is the occurrence of a characteristic form of glomerulitis, as described by Davison et aP1 Clinically, such cases demonstrate macroscopic or heavy microscopic hematuria and early renal failure. A combination of these two histologic lesions occurs least frequently. In considering the relation of hypertension to renal involvement, Rose25 concluded that the hypertension in most cases of polyarteritis is a sequel to the renal involvement (either polyarteritis or glomerulitis), but that it is not a feature of the initial phase, and that early progressive renal failure and death may antedate its appearance. The blood pressure rises during the healing or healed stages of the renal lesions, and, once initiated, the hypertension is rapidly progressive. Death, in two thirds of the patients without pulmonary involvement, is attributable to the renal lesion. In the remaining cases, demise is attributable, in the main, to coronary disease or severe gastroenteritis. Polyarteritis with Lung Involvement
This accounts for approximately one third of the cases and shows no sex predilection. Onset of systemic polyarteritis is almost invariably preceded by a respiratory illness. The duration of the preceding respiratory involvement is variable: usually less than one year, although in one quarter or more of the patients a long history (occasionally up to seven years) of respiratory infections may be elicited. That this phase of the illness is associated with the presence of specific pulmonary lesions is highly likely. A past history of rheumatic fever can be elicited in about one fifth of the patients. Clinically, the main symptoms are similar to those of asthma, pneumonia or chronic bronchitis. The asthma appears to be distinct from the usual allergic asthma in that absence of a positive family history is common, the symptoms begin at any age, it is associated with an extremely high eosinophilia, and, at necropsy, necrotizing lesions and polyarteritis of lung (and elsewhere) are usually present. The pneumonia may range in clinical severity from a transient, symptomless
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infiltration to large chronic abscesses unresponsive to antimicrobials. Hemolytic streptococci have been isolated from about one fourth of the cases. Radiologic examination shows a variable pattern of consolidation. The nose or middle ear may be occasionally involved with the typical granulomatous lesion. Severe lung changes are almost invariably present in those patients examined at necropsy. The most common (one half) lesion is the presence of nodular or caseous lesions, often resembling tuberculosis (but with absence of tubercle bacilli). Other lesions include hemorrhagic pneumonias, cavities, infarcts, fibrosis and bronchiectasis. When adequate sections have been available,25 microscopic examination has shown the characteristic necrotizing or granulomatous lesion to be present in about two thirds of the cases and pulmonary polyarteritis in about three quarters. Diffuse and focal eosinophilic infiltration was also frequently noted by these investigators. The incidence of polyarteritis in other organs and their accompanying clinical manifestations are in the main similar to those in cases without lung involvement. Hypertension occurs less frequently, and this appears to be related to the shorter survival time of subjects with lung involvement once systemic polyarteritis becomes established. In the alimentary tract, superficial ulcerations (at all levels, from mouth to colon) are more extensive and frequent. At necropsy, granulomatous lesions involving liver, kidney, spleen, lymph nodes and heart have been noted, as well as a widespread diffuse and focal eosinophilic infiltration of interstitial tissues in those in whom a high blood eosinophilia was present at the time of death. The mean total duration of the disease is longer in patients with pulmonary involvement as compared to those in whom the lungs are spared. The period of survival when dated from the onset of systemic polyarteritis, however, is less in those with pulmonary involvement. Death is attributable to the various forms of pulmonary disease in slightly less than one half of the cases and to the renal involvement in about one fourth of the cases. Polyarteritis Nodosa in the First Year of Life
Reference to the literature22 , 26 shows reports of about 20 cases of polyarteritis nodosa occurring under the age of one year. It proved to be fatal in all but two. Clinically, most of the patients had rash, pyrexia, upper respiratory tract manifestations and progressive cardiac failure or sudden death. In most, at necropsy, typical polyarteritic lesions were found to involve the skin, upper respiratory tract and heart, the maximal lesions involving the coronary arteries.
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Response to Corticoid Therapy
In May, 1960, the Collagen Disease and Hypersensitivity Panel24 of the British Medical Research Council reported on a survey involving 21 cases of histologically proved polyarteritis, treated with cortisone and followed up for three to five years. These cases were then compared with a series of untreated cases surveyed previously. At 12 months the results in the treated group are distinctly superior, although the difference between the two groups is reduced if patients entering the trial with hypertension are excluded. At three years the advantage enjoyed by the treated group has diminished and disappears entirely if patients with initial hypertension are excluded. By four years, although the numbers for comparison had fallen, the percentage of survival in the two groups is the same. Exclusion of the hypertensive patients, at this point, reveals a bias in favor of the untreated group, among whom no further deaths had taken place after the first year of disease. In view of the differences between treated and untreated groups, it is probably safer to avoid further comparison. The start of treatment certainly brought speedy and often dramatic improvement to most patients. On the other hand, it later brought distressing, unpleasant complications to a few. The trial has not produced evidence that cortisone, in the dosages given * in these patients, improved the chances of ultimate recovery; possibly it postponed death. CASE 2. T.H., a 12-year-old colored boy, was in good health until the onset of acute swelling and pain on the left side of his face. Four days later, because the swelling and pain were more severe and he had become febrile, he consulted a physician, who found an elevated temperature and gave the patient penicillin, streptomycin and demethylchlortetracyc1ine. Further progression of the symptoms, plus anorexia and malaise, necessitated hospitalization the following day. The left facial involvement subsided in a few days, only to be followed by similar involvement of the right side of the face. Over the next two weeks he had tender, hot, swollen and erythematous elbows; lower left-sided chest pain and tenderness; tender, hot, erythematous swelling of the feet and ankles (greater on the left); sloughing of skin between toes, fingers and over the elbows; bilateral knee and calf tenderness; bilateral postauricular and auricular swelling; periumbilical cramping pain; tenderness with pain on motion of the cervical and thoracic vertebrae; and a generalized, progressive, nodular erythematous eruption, particularly involving the face, arms and legs. Fever persisted despite massive antimicrobial therapy. The patient was said to have had rheumatic fever at the age of six years, though the basis for this diagnosis was uncertain in the parent's mind. On admission here the patient was noted to have pain with movement of all joints, plus periorbital edema and facial asymmetry (right side swollen). His temperature was 102 F., blood pressure 120/70, pulse 130 and respirations 30. There were denuded areas on the fingers and elbows. Firm, tender, erythematous nodules (0.5 to 1 cm. in diameter) were present over the arms and legs. The liver was palpable 4 cm. below the right costal margin and was tender. The extremities were tender to touch, particularly the calf, and muscular weakness was generalized. No definite peripheral or cranial nerve involvement was noted. ,. The numbers for comparison are small, but suggest that patients on higher doses of steroids fared better than the untreated group. 0
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Fig. 5. Photomicrograph (H & E stained) of a representative glomerulus in patient T.H. (Case 2) showing moderate diffuse hypercellularity. Hemoglobin was 6.4 gm. per 100 mI., and hematocrit 20 volumes per cent. The white blood cell count was 22,500 with 94 per cent neutrophils. A trace of proteinuria was noted, and the urine specific gravity was above 1.020. Febrile agglutination and multiple skin tests were negative. Antistreptolysin a titers on admission and three weeks later were 1250 Todd units. Numerous blood cultures were negative. Total serum protein was 5.7 gm. per 100 mI., and electrophoresis revealed the albumin to be 1.24 gm. and gamma globulin to be 2.33 gm. SGOT was 95 and SGPT 80. Examination of cerebral spinal fluid showed no cells, negative culture, and normal chemistries. Direct Coombs test result was negative, and no LE cells were seen on numerous examinations. Bone marrow examination showed an increase in mature plasma cells, some of which were binucleated and trinucleated. Skin-muscle biopsy showed a necrotizing polyarteritis, with thrombi and infiltration by histiocytes, polymorphonuclear leukocytes, plasma cells and lymphocytes. Percutaneous renal biopsy revealed medial proliferation and fibrinoid degeneration of the single arteriole seen. The glomeruli showed varying degrees of proliferative change (Fig. 5). On corticosteroid therapy, in full therapeutic dosage (e.g. 50 mg. of prednisone per square meter daily), the patient had a remission of the abnormal clinical and laboratory findings. After several months the dosage was gradually reduced to one 5-mg. tablet of prednisone four times a day, which maintained his asymptomatic state. The glucocorticoids were completely discontinued after eight months, and the patient is still asymptomatic some 13 months later. CASE 3. G.C. was a 13 7/IZ-year-old Latin American girl who had been in good health until two months before admission, when she suffered daily frontal headaches and nonprojectile, blood-streaked vomitus. Two weeks later she experienced hemoptysis and was told by her local physician that she had a "spot in her lungs" and that her stools and urine contained blood. She was found to be anemic, and two transfusions were administered.
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All symptoms continued and increased in severity until the day before admission here, when she had spontaneous epistaxis. There was no history of abdominal pain, arthralgia, fever or skin rash. Physical examination revealed a pale, chronically ill child with depression of the sensorium. Her blood pressure was normal. The remainder of the examination was normal. Laboratory studies revealed the following: hemoglobin 7.5 gm. per 100 ml., hemato· crit 19 volumes per cent, blood urea nitrogen 130 mg.; sodium 144 mEq. per liter, potassium 3.S mEq., phosphorus 7.5 mg.; antistreptolysin 0 titer 625 Todd units; and LE preparations negative on six occasions. The urine contained protein and numerous red blood cells. A study of her coagulation mechanism indicated no abnormalities. A roentgenogram of the chest revealed a questionable, but consistent, area of density in the right apex suggestive of a granulomatous lesion. The glomerular filtration rate was 5.0 cc. per minute per square meter (normal 60 to SO cc. per minute), and the effective renal plasma flow was 22 cc. per minute per square meter (normal 300 to 350 cc. per minute). After admission she was given a transfusion and her general condition transiently improved. She continued to have both hemoptysis and hematemesis, however, and her urine and stools continued to reveal active bleeding. On only one occasion did she show evidence of bleeding in other areas, and this was subconjunctival hemorrhage associated with a period of severe vomiting. Her blood pressure became elevated during the third week of hospitalization, and attempts to control it were not successful. She continued to have progression of her symptoms with evidence of pneumonitis, peripheral edema, weakness and disturbed sensorium, and expired during the sixth week of hospitalization. Findings at necropsy were those of typical extensive polyarteritis of the pulmonary involvement type as described in the text. PURPURA FULMINANS
Purpura fulminans is a rare syndrome characterized by the sudden onset of large, scattered, often symmetrically placed, ecchymotic areas principally over the legs. 28- 32 In typical patients there is rapid progression of the lesion resulting in extensive involvement of the extremities and frequently culminating in gangrene. The mortality rate is exceedingly high. 28 The disease is usually preceded by an upper respiratory tract infection of mild to moderate severity. Scarlet fever has been noted to precede the onset in 30 to 50 per cent of the reported cases, and evidence of nonerythrodermic streptococcal infection is frequently present.29 Several cases have had their onset following typical varicella. After a latent period varying between three and 30 days there is the sudden onset of ecchymotic lesions, which are initially confined to the distal portions of the legs, but spread rapidly and within a few hours may involve large areas of the extremities and trunk. The lesions are usually bluish-red with well demarcated, slightly elevated borders, and large subepidermal bullae containing a reddish-clear fluid are present in the central portions. As the ecchymotic areas progress they become confluent, and their color changes to a bluish-black. Coincident with this is the development of a brawny edema and disappearance of the arterial pulse distal to the lesion.
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Severe abdominal pain, vomiting, fever, hematochezia, oliguria, gross hematuria and peripheral vascular collapse are frequently observed. In the majority of reported cases abnormalities in coagulation have been noted. 29- 31 Most authors have noted a moderate increase in the coagulation time and a moderate reduction in circulating platelets. The prothrombin time is characteristically increased, and deficiencies of both factor V and fibrinogen have been described. 29 ,30 One recent report describes an increase in the antithrombin III factor. 31 Histologically, the involved areas reveal massive coagulation necrosis of the skin, subcutaneous tissue and skeletal muscle. Extensive microthromboses of the hyaline or fibrinoid type occlude the majority of the arteries and veins. The arterial walls generally reveal focal fibrinoid necrosis. Renal cortical necrosis has also been observed, as has occlusion of the renal artery by hyaline thrombi. Although this disease is thought to represent a hypersensitivity response, its precise relation to anaphylactoid purpura and polyarteritis is uncertain. Histologically, the lesion resembles that of thrombotic thrombocytopenic purpura, and the fulminant picture plus the occasional renal cortical necrosis suggests a relation to the generalized Shwartzman phenomenon. CASE 4. D.T., an eight-year-old white boy, was well until two weeks before admission, when he had an acute upper respiratory tract infection associated with a lowgrade fever and cough. All symptoms subsided after four days, and he remained well until seven days later, when there was the acute onset of penile and scrotal edema. Antihistaminics produced some relief. Two days later he experienced painless hematuria and noted the appearance of an erythematous, macular area on the anterior surface of both legs. There was rapid extension of these lesions within 24 hours with
Fig. 6. Photograph of lesions in D.T. (Case 4) on the day after admission, demonstrating circumscribed ecchymotic lesions with red periphery and central bullous formation.
WARREN F. DODGE, LUTHER B. TRAVIS, C. W. DAESCHNER
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Fig. 7. Photograph of patient D.T. (Case 4) 14 days later, demonstrating residual bullae and "dry" gangrene. the development of bullae. Additional erythematous lesions appeared on both proximal extremities, the lower part of the back, the axillae, and around one eye. Physical examination revealed a healthy-appearing white boy in no distress. Over the anterior and lateral surfaces of both legs there were large, well circumscribed, ecchymotic lesions with a bright red, raised periphery and central bullous formation filled with serosanguineous fluid. Additional ecchymotic lesions were located on both heels, both upper thighs, the lower sacral area, the left elbow and the left axilla. No petechial and no mucous membrane lesions were present. A brawny edema was present over the right distal extremity, and the peripheral pulses in this extremity were absent. The blood pressure was normal. Significant laboratory studies revealed the following: hemoglobin 8.2 gm. per 100 ml.; white blood cell count 18,300, with a shift to the left; platelet count 107,000, reticulocytes 2.6 per cent; urine grossly bloody; direct and indirect Coombs test results negative; stools positive for occult blood; total serum proteins 7.3 gm. per 100 ml., with an elevated gamma globulin level (2.0 gm. per 100 mI.); antistreptolysin a titer 500 Todd units. The prothrombin time was greatly prolonged, and although clotting was essentially normal, there was rapid dissolution of the clot within one hour. Other clotting factors were essentially normal with the exception of fibrinogen, which was 89 mg. per 100 ml. The child was immediately begun on massive antibiotic therapy and intravenous administration of hydrocortisone. The lesion on the right leg progressed rapidly to involve the entire lower leg and foot within 24 hours. There was a drop in hemoglobin level necessitating several transfusions. Brisk bleeding from the gastrointestinal and genitourinary tracts continued for approximately one week. There was gradual improvement of all ecchymotic areas except those of the right leg, which progressed to a "dry" gangrene. Three weeks after admission he began to pass multiple calcium phosphate stones, and x-ray films of the abdomen revealed bilateral staghorn calculi. Amputation of the right leg was performed after five weeks, and steroids were gradually discontinued without recurrence of symptoms. Histologic specimens revealed necrosis of the blood vessels and complete occlusion of both anterior and posterior tibial arteries by organizing thrombi. There were no significant changes in the walls of these vessels. The patient has continued to do well. The renal lithiasis appears, by exclusion, to be related to his prolonged bed rest.
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REFERENCES Anaphylactoid Purpura 1. Alexander, H. L., and Eyermann, C. H.: Food Allergy in Henoch's Purpura. Arch. Dermat. 6 Syph., 16:322, 1927. 2. Allen, D. M., Diamond, L. K, and Howell, D. A.: Anaphylactoid Purpura in Children (SchOnlein·Henoch Syndrome). Am. J. Dis. Child., 99:833, 1960. 3. Bergstrand, A., Bergstrand, C. G., and Bucht, H.: Kidney Lesions Associated with Anaphylactoid Purpura in Children. Acta Pediat., 49:57, 1960. 4. Derham, R. J., and Rogerson, M. M.: The Sch1inlein·Henoch Syndrome, with Particular Reference to Renal Sequelae. Arch. Dis. Childhood, 31: 364, 1956. 5. Dodge, W. F., Daeschner, C. W., Brennan, J. C., Rosenberg, H. S., Travis, L. B., and Hopps, H. C.: Percutaneous Renal Biopsy in Children. II. Acute Glomeru· lonephritis, Chronic Glomerulonephritis, and Nephritis of Anaphylactoid Purpura. Pediatrics, 30:297, 1962. 6. Gairdner, D.: The Sch1inlein-Henoch Syndrome (Anaphylactoid Purpura). Quart. J. Med., 17:95, 1948. 7. Komrower, G.: Discussion of T. K Oliver and H. L. Barnett. 1o A.M.A. J. Dis. Child., 90:546,1955. 8. Levitt, L. M., and Burbank, B.: Glomerulonephritis as a Complication of the SchOnlein-Henoch Syndrome. New England J. Med., 248:530, 1953. 9. Lewis, I. C.: The SchOnlein-Henoch Syndrome (Anaphylactoid Purpura) Com· pared with Certain Features of Nephritis and Rheumatism. Arch. Dis. Child· hood, 30:212, 1955. 10. Oliver, T. K, and Barnett, H. L.: The Incidence and Prognosis of Nephritis Associated with Anaphylactoid Purpura (SchOnlein-Henoch Syndrome) in Chilo dren. A.M.A. J. Dis. Child., 90:544, 1955. 11. Osler, W.: The Visceral Lesions of Purpura and Allied Conditions. Brit. M.J., 1:517, 1914. 12. Panos, T. C.: Anaphylactoid Purpura in Children; in Mesenchymal Diseases in Childhood. 21st Pediatric Research Conference, Ross Laboratories, 1957, pp. 88-92. 13. Philpott, M. G.: The SchOnlein-Henoch Syndrome in Childhood, with Particular Reference to the Occurrence of Nephritis. Arch. Dis. Childhood, 27:480, 1952. 14. Philpott, M. G., and Briggs, J. N.: Treatment of the SchOnlein-Henoch Syndrome with A.C.T.H. and Cortisone. Arch. Dis. Childhood, 28:57, 1953. 15. Rubin, M. 1.: Discussion of paper by Oliver et al. Am. J. Dis. Child., 90:545, 1955. 16. Starky, G., and Thileu, A.: A Study on the Onset and Prognosis of Acute Vascular Purpura (the Sch1inlein-Henoch Syndrome) in Children. Acta Pediat., 49:217,1960. 17. Vernier, R. L., Worthen, H. G., Peterson, R. D., Colle, E., and Good, R. A.: Anaphylactoid Purpura. I. Pathology of the Skin and Kidney and Frequency of Streptococcal Infection. Pediatrics, 27:181, 1961. 18. Wedgwood, R. J. P., and Klaus, M. H.: Anaphylactoid Purpura (Sch1inleinHenoch Syndrome). A Long Term Follow-up Study with Special Reference to the Renal Lesion. Pediatrics, 16:196, 1955. Polyarteritis Nodosa 19. Black, R. L.: Polyarteritis Nodosa. Postgrad. Med., 31:426, 1962. 20. Idem: The Characterization of Polyarteritis Nodosa, Dermatomyositis and Pro· gressive Systemic Sclerosis. M. Clin. N. Amer., 45:1295, 1961. 21. Davison, J., Ball, J., and Platt, R.: The Kidney in Periarteritis Nodosa. Quart. J. Med., 17:175, 1948. 22. Henry, M. J., Stoeckle, H. G., and Hopps, H. C.: Periarteritis in a 4-Month-Old Infant Unresponsive to Penicillinase. Am. Heart J., 60:817, 1960. 23. Moore, R. H., and Movat, H. Z. The Significance of Plasma Cells in the Lesions of Acute Polyarteritis. J. Path. 6 Bact. (London), 75:127,1958.
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24. Treatment of Polyarteritis Nodosa with Cortisone: Results after Three Years. Report to the Medical Research Council by the Collagen Disease and Hyper· sensitivity Panel. Brit. M.f., 5183,1399, 1960. 25. Rose, G.A.: Natural History of Polyarteritis. Brit. M.J., 2:1148, 1957. 26. Savage, T. R., and Smith, J. F.: Polyarteritis Nodosa and Congenital Pyloric Hy· pertrophy in a 3·Month·Old Infant. J. Clin. Path., 13:291, 1960. 27. Zeek, P. M.: Periarteritis Nodosa and Other Forms of Necrotizing Angiitis. New England J. Med., 248:764, 1953. Purpura Fulminans
28. Crawford, S. E., and Riddler, J. G.: Purpura Fulminans. Am. J. Dis. Child., 97: 198, 1959. 29. Dyggve, H.: A Case of Purpura Fulminans with Fibrinogenopenia in Association with Scarlatina. Acta Med. Scand., 127:382, 1947. 30. Feldman, R., Lubby, A. L., and Sala, A. M.: Purpura Fulminans, Thrombotic Thrombocytopenic Purpura and the Shwartzman Phenomenon. Am. J. Dis. Child., 100:587, 1960. 3l. McKay, G. F., Pisciotta, A. V., and Johnson, S. A.: Homeostatic Mechanisms, Antithromin and Purpura Fulminans. Am. J. Clin. Path., 38:357, 1962. 32. Turin, R. D., Mandel, S., and Hornstein, L.: Fulminating Purpura with Gangrene of Lower Extremity Necessitating Amputation. J. Pediat., 54:206, 1959. University of Texas Medical Branch Galveston, Texas